Diabetes mellitus (DM) is of major epidemiological importance, accounting for a high incidence of heart failure in these patients. Hyperglycemia, as an independent risk factor, directly causes cardiac damage and leads to diabetic cardiomyopathy. Apart from the mechanisms of DM-induced cardiac remodeling, little is known about the transition from compensated cardiomyopathy to heart failure. It has been shown that DM also affects the metabolic availability of vitamin A. Activation of RXR-mediated signaling improves insulin resistance in type 2 DM, indicating that RA signaling is involved in the development of DM. Elevated activity of the RAS is associated with progression of cardiac remodeling and a poor prognosis in patients with DM. Suppression of the RAS, using angiotensin converting enzyme (ACE) inhibitors (ACEI) and AT1R blockers (ARBS), has been shown to reduce cardiovascular events. However, interrupting the RAS with a single-site inhibitor, often does not achieve complete and long-lasting pharmacological blockade. The generation of Ang II remains unopposed during AT1R-blockade and leaves the potential for stimulation of other Ang II receptors108. ACE inhibitors may not suppress the production of Ang II completely, since there are ACE-independent mechanisms for Ang II production. We have recently demonstrated that RA suppresses hypertrophic stimuli-induced production of Ang II and cardiac expression of renin, Ao, ACE and AT1R and upregulates the expression of ACE2. By inhibiting the rate-limiting step in the RAS cascade, RA might have advantages over ACEI and ARBs. Our data demonstrate that RA suppresses hyperglycemia induced cardiomyocyte growth, apoptosis, and intracellular ROS generation. High-glucose induced expression of Kruppel-like factor 5 (KLF5) and nuclear translocation of NF-?B was blocked by RA. These observations are extremely important in that KLF5, as an upstream mediator of NF-?B, has been demonstrated to be involved in both Ang II and pressure-overload induced cardiac remodeling. Additionally, members of the KLF family have been found to be involved in Type 2 DM. A tenable hypothesis is that abnormal expression and/or activation of RA signaling in the diabetic heart is associated with increased oxidative stress, enhanced expression of RAS components and activation of KLF5/NF-?B mediated signaling. Targeted activation of RA signaling may prevent DM-induced development of cardiac remodeling, by reducing oxidative stress and through inhibition of expression of RAS components and associated signaling. We propose using in vitro cultured neonatal cardiac myocytes and fibroblasts and in vivo Zucker Diabetic Fatty rats, to determine the effect of DM on the expression/activation of RA signaling, address the molecular mechanisms of RA-mediated signaling in DM-induced cardiac remodeling and determine the regulatory mechanisms of RA signaling on DM-induced expression/activation of RAS components. Identifying the specific molecular mechanisms of RA signaling, involved in DM-mediated cellular effects, may provide an alternative approach for developing improved therapies for patients with DM and related cardiac complications. PUBLIC HEALTH RELEVANCE: Our proposal focuses on determining the molecular mechanisms whereby retinoid receptor-mediated signaling regulates diabetes mellitus-induced cardiac remodeling. This may lead to the development of novel strategies for the prevention and treatment of cardiac related diabetic complications.